Gene therapy has vast potential for treating and potentially curing a wide variety of disorders. However, gene delivery technologies require significant improvements in safety, efficiency, and expression stability before the majority of these diseases can be treated. Vectors based on adeno-associated virus (AAV) have proven themselves to be highly promising, both in the laboratory and the clinic, but they still suffer from several shortcomings. In particular, they are unable to readily target gene delivery to specific cell types, and their efficiency is compromised by their recognition and neutralization by the immune system. These two liabilities are a result of the surface properties of this virus, and we will implement a combined chemical synthesis and molecular biology approach to engineer the viral surface for targeted gene delivery and enhanced stealth. Specifically, the genetic insertion of a peptide tag into the viral capsid will allow the modular and reversible attachment of chemically synthesized targeting peptides and stealthing polymers. In effect, this already effective product of nature is being engineered to better match human therapeutic needs. The Specific Aims are: 1. To determine whether a combined, modular chemical and genetic approach can effectively target AAV gene delivery 2. To determine whether polyethylene glycol can "stealth" AAV from neutralizing antibodies The novel blend of synthetic chemistry, molecular biology, and bioengineering described in this proposal will be well suited to addressing this problem at the interface of engineering and medicine. [unreadable] [unreadable]